PORTLAND, Ore. -- Gleevec (imatinib) has led to an overall 60-month survival rate of 95% for chronic myeloid leukemia (CML) patients with who took the tyrosine kinase inhibitor daily, found an international study. Yet the drug doesn't cure the disease.
PORTLAND, Ore., Dec. 7 -- Gleevec (imatinib) has led to an overall survival rate of 95% for chronic myeloid leukemia (CML) patients who took the tyrosine kinase inhibitor daily for 60 months, according to an international study.
Nevertheless, while Gleevec showed a remarkable ability to contain CML, it has not been able to cure the disease, reported Brian Druker, M.D., of the Oregon Health and Science University here, and colleagues in the International Randomized Study of Interferon and ST1571 (IRIS).
"It is currently recommended that imatinib therapy be continued indefinitely," they wrote in the Dec. 7 issue of the New England Journal of Medicine, citing anecdotal reports of relapse when the drug was stopped.
There were relapses even by patients in whom there were lengthy periods of complete molecular response, with undetectable levels of the Philadelphia chromosome by polymerase chain reaction (PCR). "It is not known why imatinib is not able to eradicate the malignant clone," they added.
Of 553 patients originally randomized to Gleevec in the IRIS trial, 382 patients were still taking Gleevec at 60 months, and of these 368 (96%) had a complete cytogenetic response, according to the study.
The finding of "durable responses in a high proportion of CML patients," came from the five-year follow-up of the original 19-month IRIS cross-over study of Gleevec versus interferon alfa plus Ara-C (cytarabine), said Dr. Druker.
The original study of 1,106 patients with Philadelphia chromosome-positive CML showed a high rate of response and an acceptable rate of side effects for Gleevec (400 mg orally daily). The drug is a relatively specific inhibitor of the BCR-ABL tyrosine kinase. At the outset, 553 patients were assigned to daily Gleevec and 553 to receive interferon alfa plus Ara-C.
In the early IRIS trial, patients were allowed to cross over to the alternative treatment, and most patients in the interferon group either switched to Gleevec or discontinued interferon, making it impossible to compare the two treatments in the extended study.
However, previous studies, before the availability of Gleevec, had shown a five-year survival rate for interferon alfa plus Ara-C of 68% to 70%, making it possible to demonstrate a five-year survival advantage for Gleevec.
In the long-term analysis of 553 newly diagnosed patients randomly assigned to Gleevec, at a median follow-up of 60 months, Kaplan-Meier estimates of complete cytogenetic response were 69% by 12 months and 87% by 60 months.
With a median follow-up of 60 months, the estimated relapse rate was 17%, while an estimated 7% of all patients progressed to accelerated-phase CML or blast crisis.
The estimated overall survival at 60 months of patients who received Gleevec as initial therapy was 89% (95% CI, 86-92), a rate higher than that reported in any previously published prospective study of the treatment of CML, the researchers said.
After data were adjusted for patients who had died from causes unrelated to CML or stem-cell transplantation, the overall estimated survival rate was 95% (95% CI 93-98) at 60 months.
Finally, 97% of patients with a complete cytogenic response within 12 months after starting Gleevec did not progress to the accelerated phase or blast crisis by 60 months, the investigators found.
Notably, the researchers said that patients considered at high risk on the basis of Sokal scores had a lower rate of complete cytogenic response (69%) than did patients who were at low or intermediate risk (89% and 82% respectively).
However, the risk of relapse in patients with a cytogenic response was not associated with Sokal score, whereas with interferon treatment the Sokal score was important even among patients with a complete cytogenic response.
Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001).
Remarkably, the researchers said, no patient who had a complete cytogenic response and a reduction in levels of BCR-ABL transcripts of at least 3 log at 12 or 18 months after starting Gleevec had progression of CML by 60 months.
In a review of adverse events with the drug, the investigators reported that at a median follow-up of 60 months, grade 3 or 4 adverse events diminished over time and did not change in profile. These events included neutropenia (17%), thrombocytopenia (9%), anemia (4%), elevated liver enzymes (5%), and other drug-related adverse events (17%). One patient had drug-related congestive heart failure.
Other commonly reported adverse events included edema (60%) as well as muscle cramps, diarrhea, nausea, musculo-skeletal pain, abdominal pain, fatigue, joint pain, and headache.
Notably, Dr. Drucker said, the rate of disease progression in patients in this study is trending downward, although the trend has not reached statistical significance. If it persists, such a trend would be consistent with the findings that mutations in BCR-ABL genes are the major cause of relapse in Gleevec patients.
In a research paper in the same NEJM issue, Klaus Strebhardt, Ph.D., of J.W. Goethe University in Frankfurt Germany, and Axel Ullrich, Ph.D., of the Max Plank Institute of Biochemistry in Martinsried, Germany, wrote that Gleevec has an "astonishing" efficacy in CML, and clinical studies have not shown substantial toxic effects.
Nevertheless, they said, as with other cytotoxic therapies, the benefits of treatment with Gleevec are accompanied by adverse effects that must be managed to facilitate a patient's adherence to therapy.
Among the adverse effects mentioned in studies are left ventricular dysfunction and congestive heart failure in 10 patients, with a severe drop in ejection fraction during therapy.
They also noted that several conditions of cellular stress, such as perturbation of calcium homeostasis or the redox status, can lead to the accumulation of misfolded proteins in the lumen of the endoplasmic reticulum, activation of the endoplasmic reticulum stress response, and, consequently cell death.
Targeting the array of kinases in cancer is a rapidly expanding strategy for developing drugs for the treatment of cancer, they said.
"A reevaluation of the considerable data available for small-molecule inhibitors, such as imatinib, is necessary," they said.
Also, they added, underscoring this need are the observations that c-ABL mediates the tumor-suppressor effects of the EphB4 receptor in breast cancer cells and that Gleevec impairs this cellular defense.
"The potential of imatinib to promote epithelial tumor progression and to induce heart failure should not be ignored in future clinical trials," they concluded.
In a letter in the same NEJM issue , Andrew Grey, M.D., of the University of Auckland in New Zealand, and colleagues, discussed the issue of hypophosphatemia, with low-normal serum calcium levels, elevated levels of parathyroid hormone, and low-normal bone turnover that may occur in the early stages of therapy with Gleevec. These effects were reported in a recent issue of the journal.
"We suggest," Dr. Gray and colleagues said, "that the hypophosphatemia associated with the use of imatinib results from secondary hyperparathyroidism. Long-term studies of the effects of imatinib on bone metabolism and bone density are warranted."
In citing financial disclosures, Dr. Drucker reported that his institution is the site of clinical trials sponsored by Novartis, maker of Gleevec, but that neither he nor his laboratory received funds from Novartis. Other IRIS investigators reported receiving consulting, lecture, or grant fees from Novartis, Bristol-Myers Squibb, MGI Pharma, Pharmion, Novartis Oncology, Pfizer, Amgen, Celgene, Merck, LymphoSign, and Schering. Dr. Charlene So, reported that she is an employee of Novartis and has equity ownership in Novartis and Pfizer; Laurie Letvak, M.D., reported being an employee of Novartis and having equity ownership in the company, while Insa Gathmann reported being an employee of Novartis and having equity ownership in the company.
Co-authors Ian Reid, M.D., and Peter Browwett, M.B., reported receiving research funding and consulting fees from Novartis.
Dr. Ulrich reported receiving lecture fees from Pfizer.